The number and proportion of elderly (greater than 65 yr) within the U.S. continues to increase, along with the disproportionate use of drugs in this population, The elderly often respond differently to drugs than younger patients, and this is related in a greater incidence of adverse reactions. The overall goal of the proposed research is to gain insight into the role and importance of altered drug disposition/pharmacokinetics and pharmacodynamics in age-related changes in drug responsiveness in man. Such information should lead to more rational and safer drug use in the elderly. Depression is the most common cause of mental illness in the elderly, and tricyclic antidepressant use is high. Doxepin (Sinequan, Adipan) is widely prescribed in the elderly but, in contrast to other commonly used drugs, little is known of the effects of age on its disposition and how such changes contribute to the increased side-effects in older patients. Studies are, therefore, planned to compare the disposition of doxepin and its psychoactive metabolite, N-desmethyl-doxepin, in young and elderly subjects. Because doxepin is administered as a 15:85 mixture of cis and trans isomers, investigations are also planned to determine the mechanism of the apparent inversion of this ratio occurring during formation of the N-demethylated metabolite. Studies will also be performed to determine the contribution of polymorphic oxidative metabolism in the large interindividual variability in the disposition of this antidepressant. Increased CNS sensitivity to drugs is often present in the elderly. Because drug levels in the brain are determined by transport across the blood-brain-barrier-, investigations will be continued to study factors involved in such transport. Of particular interest will be the role of plasma binding and the mechanism whereby dissociation of the bound complex is enhanced in vivo compared to that in vitro. Studies are planned to examine the effect of different binding macro-molecules on this phenomenon and the relationship between unbound drug concentrations in the plasma and those in the brain as measured by technique of in situ intracranial dialysis. Aging leads to a decrease in beta adrenoreceptor responsiveness in animals and humans. Studies with leukocytes sugggest that this involves a functional uncoupling of the receptor adenylate cyclase system without a change in the number of receptors. The elderly also have an impaired ability to regulate this receptor's affinity for agonists in response to physiological stimuli. Studies are planned to determine the mechanism of beta receptor functioning in the elderly and how this differs from that in younger individuals. Investigations will also determine whether the receptor changes seen in the leukocyte are generalizable, especially to the vascular bed, and how this affects hemodynamics.